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Updated: Jul 12, 2025
Isolation of Macrophage Subsets and Stromal Cells from Human and Mouse Myocardial Specimens
Published on: December 17, 2019
Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative
Jiaqi He1,2, Lan Wei1,2, Shengan Tan1,2
1State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)-induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild-type mice. Our data suggest that mice with macrophage-specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co-culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast-to-myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.
Insights
Receptor for advanced glycation end products (RAGE) in macrophages promotes cardiac fibrosis by activating alternatively activated macrophages via autophagy. Blocking RAGE may treat heart failure.
Area of Science:
- Cardiovascular Research
- Immunology
- Cell Biology
Background:
- Myocardial fibrosis (MF) is a key factor in heart failure (HF).
- Alternatively activated macrophages contribute to fibrosis and tissue remodeling.
- The role of macrophage receptor for advanced glycation end products (RAGE) in cardiac fibrosis is unclear.
Purpose of the Study:
- To investigate the role of macrophage RAGE in transverse aortic constriction (TAC)-induced myocardial fibrosis.
- To determine if RAGE deficiency in macrophages protects against pressure overload-induced cardiac dysfunction and fibrosis.
Main Methods:
- Utilized a mouse model of transverse aortic constriction (TAC) to induce pressure overload.
- Employed RAGE knockout mice and macrophage-specific RAGE deletion models.
- Conducted in vitro studies using RAW264.7 macrophages and cardiac fibroblasts, including co-culture systems.
- Assessed macrophage polarization, autophagy activation, fibroblast-to-myofibroblast transition (FMT), cardiac hypertrophy, and fibrosis.
Main Results:
- RAGE expression was upregulated in alternatively activated macrophages in TAC-induced mouse hearts.
- RAGE knockout mice exhibited reduced macrophage infiltration, cardiac hypertrophy, and fibrosis.
- Macrophage-specific RAGE deletion protected against pressure overload-induced cardiac dysfunction and interstitial fibrosis.
- RAGE deficiency inhibited alternatively activated macrophage differentiation by suppressing autophagy.
- Macrophage polarization toward an alternatively activated phenotype promoted fibroblast activation, which was reduced by RAGE or autophagy inhibition.
Conclusions:
- Macrophage RAGE signaling plays a critical role in the recruitment and activation of alternatively activated macrophages through autophagy regulation.
- This process contributes significantly to myocardial fibrosis and cardiac dysfunction under pressure overload.
- Targeting RAGE signaling presents a potential therapeutic strategy for hypertensive heart disease and related conditions.
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